Chronic metformin pre-treatment dose-dependently decreased doxorubicin sensitivity in H9c2 cardiomyoblast cells, increasing the IC50 from 0.164 µM to 0.51 µM at 2.8 mM metformin.
Does chronic metformin exposure alter doxorubicin sensitivity and genome-wide DNA methylation in H9c2 cardiomyoblast cells?
Chronic metformin exposure induces dose-dependent DNA methylation remodeling and reduces doxorubicin sensitivity in cardiomyoblast cells, suggesting a potential epigenetic mechanism for protection against chemotherapy-induced cardiotoxicity.
Background/Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by dose-dependent cardiotoxicity. Emerging evidence suggests that epigenetic dysregulation, particularly altered DNA methylation, contributes to DOX-induced cardiac injury. Metformin has been reported to exert cardiometabolic and epigenetic regulatory effects. This study investigated genome-wide DNA methylation changes induced by chronic metformin exposure and their effects on doxorubicin sensitivity in H9c2 cardiomyoblast cells. Methods: Genome-wide DNA methylation changes induced by chronic metformin exposure were investigated in H9c2 cardiomyoblast cells using whole-genome bisulfite sequencing (WGBS). Cells were treated with metformin (0.7–2.8 mM) for four months prior to DOX exposure. Cellular sensitivity to DOX was evaluated using MTT-based dose–response analysis and IC50 estimation. Results: DOX reduced cell viability (IC50 = 0.164 µM). Chronic metformin pre-treatment produced a dose-dependent rightward shift in DOX dose–response curves, increasing IC50 values to 0.21, 0.289, and 0.51 µM at 0.7, 1.4, and 2.8 mM metformin, respectively. WGBS revealed distinct separation between treatment groups in principal component analysis. Significant methylation changes (adjusted p-value < 0.05) were identified in genes related to oxidative stress, mitochondrial function, apoptosis, and chromatin regulation. Conclusions: Chronic metformin exposure induces dose-dependent genome-wide DNA methylation remodeling in cardiac cells and is associated with altered cellular sensitivity to doxorubicin. These findings suggest that metabolic modulation by metformin may influence epigenetic regulation and cellular stress responses relevant to chemotherapy-induced cardiotoxicity.
Shayeb et al. (Fri,) conducted a other in Doxorubicin-induced cardiotoxicity. Metformin vs. No metformin pre-treatment was evaluated on Cellular sensitivity to doxorubicin (IC50). Chronic metformin pre-treatment dose-dependently decreased doxorubicin sensitivity in H9c2 cardiomyoblast cells, increasing the IC50 from 0.164 µM to 0.51 µM at 2.8 mM metformin.